CN107056781A - A kind of synthetic method of the formaldoxime of (E) 5 methyl 1H pyrrolo-es [2,3 b] pyridine 3 - Google Patents

A kind of synthetic method of the formaldoxime of (E) 5 methyl 1H pyrrolo-es [2,3 b] pyridine 3 Download PDF

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Publication number
CN107056781A
CN107056781A CN201710351919.9A CN201710351919A CN107056781A CN 107056781 A CN107056781 A CN 107056781A CN 201710351919 A CN201710351919 A CN 201710351919A CN 107056781 A CN107056781 A CN 107056781A
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Prior art keywords
compound
pyrrolo
pyridine
formaldoximes
methyl isophthalic
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CN201710351919.9A
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马敬祥
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Kang (shanghai) New Medicine Research & Development Co Ltd
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Kang (shanghai) New Medicine Research & Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention relates to a kind of synthetic method of the formaldoxime of (E) 5 methyl 1H pyrrolo-es [2,3 b] pyridine 3.Mainly solve to have no the technical problem of its efficient synthesis now.Synthetic method of the present invention comprises the following steps：The bromination of the picoline of 2 amino 5, obtains compound 1；Compound 1 is under the conditions of Sonogashira coupling reactions, and trimethyl acetenyl pasc reaction generation compound 2；Compound 2 and sodium hydride reaction, form pyrrole ring, generate compound 3；Compound 3 and methenamine reaction, generate compound 4；Compound 4 and hydroxylamine hydrochloride, acetic acid sodium reaction obtain the formaldoxime of target product (E) 5 methyl 1H pyrrolo-es [2,3 b] pyridine 3.As medicine intermediate, it is used widely in pharmaceutical industry.

Description

The synthesis of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes Method
Technical field
The present invention relates to the synthesis of (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes.
Background technology
(E) -5- methyl isophthalic acids H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes（CAS：1198098-52-0）As in medicine Mesosome, is used widely in pharmaceutical industry.But so far on the not disclosed report of its synthetic method.
The content of the invention
It is an object of the invention to provide the synthesis of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes Method, mainly solves to have no the technical problem of its efficient synthesis now.
Technical solution of the present invention is：The synthesis side of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes Method, it is characterized in that including lower step：The first step, 2- amino -5- picolines are in dichloromethane and bromine reaction, room temperature reaction, Saturated sodium bisulfite solution removes unnecessary bromine, obtains compound 1；Second step, the Yuan heads of compound 1（Sonogashira）It is even Join under reaction condition, diisopropylamine (DIPA) is used as catalysis as solvent and alkali, bi triphenyl phosphorus palladium chloride and cuprous iodide Agent system, and trimethyl acetenyl silicon heating stirring are stayed overnight, and obtain compound 2, and product is directly used in next step anti-without purifying Should；3rd step, in 1-METHYLPYRROLIDONE（NMP）In, compound 2 and the reaction of sodium hydride heating stirring generate compound 3, production Product pass through recrystallization purifying；The mixed liquor of 4th step, water and acetic acid is used as solvent, compound 3 and methenamine reaction, reaction solution It is heated to reflux, generates compound 4, product is separated by silica gel column chromatography；5th step, compound 4 is first dissolved by heating in methyl alcohol, Room temperature is subsequently cooled to, hydroxylamine hydrochloride and sodium acetate is added, reacts at room temperature, obtain target product 5, target product is through overweight Crystallization purifying.
Synthetic line is as follows：
。
The first step reaction time is 10-30 minutes, preferably 20 minutes；70-90 DEG C of second step reaction temperature, preferably 80 DEG C； The three-step reaction time is 5-15 minutes, preferably 10 minutes, preferably 70-90 DEG C of three-step reaction temperature, 80 DEG C；Four-step reaction Time is 3-5 hours, preferably 4 hours；5th step is reacted, and compound 4 first heats 60-70 DEG C of dissolving in methyl alcohol, adds hydrochloric acid Azanol and sodium acetate, react 5-15 minutes, preferably 10 minutes at room temperature.
The beneficial effects of the invention are as follows：In whole building-up process, raw material is cheap, intermediate and target product purifying letter It is single.
Specific embodiment
Embodiment 1：
Step 1：
2- amino -5- picolines are added into three-necked flask（70.0 g, 654 mmol）, dichloromethane（150 mL）； Bromine is added in ice bath（36.0 mL, 698 mmol）.Reaction solution is stirred at room temperature 30 minutes.Add saturated sodium sulfite molten Liquid（100 mL）；Aqueous phase dichloromethane（100 mL x 3）Extraction, organic phase merges, and uses water（100 mL）And saturated common salt Water（100 mL）Washing, sodium sulphate is dried, filtering.It is spin-dried for obtaining yellow solid, compound 1（103.0 g, 550 mmol, 84 %）.Product is directly used in next step reaction.1H NMR (400 MHz, CDCl3) 2.18 (s, 3H), 4.89 (br, 2H), 7.51 (d, J = 1.2 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H) ppm；
Step 2：
Compound 1 is added into three-necked flask（55.4 g, 300 mmol）, diisopropylamine（60 mL）, trimethyl acetenyl Silicon（60 mL, 420. 0 mmol）, bi triphenyl phosphorus palladium chloride（2.04 g, 2.9 mmol）And cuprous iodide（0.55 g, 2.9 mmol）；Under nitrogen protection, 80 degrees Celsius are stirred overnight reaction solution.Reaction solution is cooled to room temperature, is filtered to remove and urges Agent.It is spin-dried for obtaining crude product, in ethyl acetate（50 mL）In be recrystallized to give brown solid, compound 2（49.2 g, 241.2 mmol, 80 %）.1H NMR (400 MHz, CDCl3) 0.26 (s, 9H), 2.05 (s, 3H), 4.95 (br, 2H), 7.39 (d, J = 1.6 Hz, 1H), 7.84 (s, 1H) ppm；
Step 3：
Compound 2 is added into three-necked flask（9.8 g, 48.0 mmol）And 1-METHYLPYRROLIDONE（50 mL）；In ice bath Middle addition sodium hydride（60 %, 2.8 g, 59 mmol）, 100 degrees Celsius are stirred 10 minutes.Room temperature is cooled to, saturation chlorine is added Change ammonium salt solution（50 mL）, ethyl acetate extraction（50 mL x 3）;Organic phase merges, and uses water（100 mL）And saturated aqueous common salt （100 mL）Washing, sodium sulphate is dried, filtering.Filtrate is spin-dried for obtaining crude product, in ethyl acetate（10 mL）In recrystallize To white solid, compound 3（5.1 g, 38.6 mmol, 80 %）.1H NMR (300 MHz, DMSO-d6) 2.34 (s, 3H), 6.34 (s, 1H), 7.40 (s, 1H), 7.57 (s, 1 H), 7.71 (s, 1H), 8.05 (s, 1H), 11.48 (s, 1H) ppm；
Step 4：
Compound 3 is added into three-necked flask（0.50 g, 3.8 mmol）, methenamine（0.8 g, 5.7 mmol）, water（5 mL）And acetic acid（2.5 mL）；Reaction solution is heated to reflux 4 hours.Reaction solution is cooled to room temperature, ethyl acetate extraction（30 mL x 3）;Organic phase merges, and uses saturated aqueous common salt（30 mL）Washing, sodium sulphate is dried, filtering.Filtrate is spin-dried for, crude product purified by silica gel Pillar layer separation（Petroleum ether：Ethyl acetate volume ratio=1:2）, obtain faint yellow solid, compound 4（0.3 g, 1.9 mmol, 49 %）.1H NMR (300 MHz, DMSO-d6) 2.42 (s, 3H), 8.25 (m, 2H), 8.41 (s, 1H), 9.89 (s, 1H), 12.60 (br, 1H) ppm；
Step 5：
Compound 4 is added into three-necked flask（1.8 g, 11.2 mmol）, methanol（20 mL）, be heated to 65 degrees Celsius it is molten Solution；Room temperature is cooled to, hydroxylamine hydrochloride is added（1.0 g, 14.4 mmol）And sodium acetate（1.2 g, 15. 0 mmol）, reaction Liquid is stirred at room temperature 10 minutes.Add water（40 mL）, white solid is collected by filtration, and uses dichloromethane（10 mL x 3）Washing, does It is dry, obtain target compound 5（1.4 g, 8.0 mmol, 71 %）.1H NMR (300 MHz, DMSO-d6) 2.39 (s, 3H), 7.70 (d, J = 2.7 Hz, 1H), 8.09 (s, 1H), 8.12 (d, J = 1.8 Hz, 1H), 8.22 (s, 1H), 10.63 (s, 1H), 11.81 (br, 1H) ppm。
Embodiment 2：The first step reaction time is 10 minutes；90 DEG C of second step reaction temperature；The three-step reaction time is 15 Minute, three-step reaction temperature 70 C；The four-step reaction time is 3 hours；5th step is reacted, and compound 4 first adds in methyl alcohol 60 DEG C of dissolvings of heat, add hydroxylamine hydrochloride and sodium acetate, react 15 minutes at room temperature.Remaining be the same as Example 1.
Embodiment 3：The first step reaction time is 30 minutes；70 DEG C of second step reaction temperature；The three-step reaction time is 5 points Clock, 90 DEG C of three-step reaction temperature；The four-step reaction time is 5 hours；5th step is reacted, and compound 4 is first heated in methyl alcohol 70 DEG C of dissolvings, add hydroxylamine hydrochloride and sodium acetate, react 5 minutes at room temperature.Remaining be the same as Example 1.

Claims (9)

  1. The synthetic method of one kind 1. (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes, it is characterized in that including with Lower step：The first step, the bromination of 2- amino -5- picolines, obtains compound 1；Second step, Yuan couplings of 1 of compound are anti- Under the conditions of answering, and trimethyl acetenyl pasc reaction generation compound 2；3rd step, compound 2 and sodium hydride reaction, generate chemical combination Thing 3；The mixed liquor of 4th step, water and acetic acid generates compound 4 as solvent, compound 3 and methenamine reaction；5th step, Compound 4 and hydroxylamine hydrochloride, acetic acid sodium reaction, obtain target product 5；Synthetic line is as follows：
    。
  2. 2. the conjunction of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes according to claim 1
    Into method, it is characterized in that the first step is reacted in dichloromethane.
  3. 3. the conjunction of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes according to claim 1
    Into method, it is characterized in that the first step and bromine are reacted 10-30 minutes at room temperature.
  4. 4. the conjunction of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes according to claim 1
    Into method, it is characterized in that second step 70-90 DEG C of reaction in diisopropylamine.
  5. 5. the conjunction of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes according to claim 1
    Into method, it is characterized in that second step reacts under bi triphenyl phosphorus palladium chloride and cuprous iodide catalysis.
  6. 6. the conjunction of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes according to claim 1
    Into method, it is characterized in that the 3rd step is in 1-METHYLPYRROLIDONE, 70-90 DEG C is reacted 5-15 minutes.
  7. 7. the conjunction of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes according to claim 1
    Into method, it is characterized in that heating reflux reaction 3-5 hours.
  8. 8. the conjunction of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes according to claim 1
    Into method, it is characterized in that the 5th step compound 4 heats 60-70 DEG C of dissolving in methyl alcohol.
  9. 9. the conjunction of one kind (E) -5- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -3- formaldoximes according to claim 1
    Into method, it is characterized in that the 5th step compound 4 and hydroxylamine hydrochloride and sodium acetate react 5-15 minutes at room temperature.
CN201710351919.9A 2017-05-18 2017-05-18 A kind of synthetic method of the formaldoxime of (E) 5 methyl 1H pyrrolo-es [2,3 b] pyridine 3 Withdrawn CN107056781A (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN109232562A (en) * 2018-10-24 2019-01-18 康化（上海）新药研发有限公司 A kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5-

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CN1078469A (en) * 1992-05-13 1993-11-17 森得克斯(美国)股份有限公司 Substituted indole, the assorted indoles of ammonia and tetrahydro-1 H-pyrrolo be [2,3-c] pyridin-7-one derivatives also
CN1225085A (en) * 1996-07-18 1999-08-04 麦克弗罗斯特(加拿大)有限公司 Substituted pyridines as selective cyclooxygenase-2 inhibitors
WO2008004117A1 (en) * 2006-07-06 2008-01-10 Pfizer Products Inc. Selective azole pde10a inhibitor compounds
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CN1078469A (en) * 1992-05-13 1993-11-17 森得克斯(美国)股份有限公司 Substituted indole, the assorted indoles of ammonia and tetrahydro-1 H-pyrrolo be [2,3-c] pyridin-7-one derivatives also
CN1225085A (en) * 1996-07-18 1999-08-04 麦克弗罗斯特(加拿大)有限公司 Substituted pyridines as selective cyclooxygenase-2 inhibitors
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109232562A (en) * 2018-10-24 2019-01-18 康化（上海）新药研发有限公司 A kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5-

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